Metal-Binding Q-Proline Macrocycles

Northrup, Justin D.; Wiener, Jesse; Hurley, Margaret M.; Hou, Chun-Feng David; Keller, Taylor; Baxter, Richard; Zdilla, Michael J.; Voelz, Vincent A.; Schafmeister, Christian E.

doi:10.26434/chemrxiv.13554731

Cited by 4 publications

(14 citation statements)

References 3 publications

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“…More recently, this approach was used to determine the solution-state structure and ion-binding mechanism of cyclic peptoid-spiroligomer hexamer macrocycles (Hurley et al, 2021). Northrup et al found that particular sequences of alternating Q-proline and peptoid residues are able to bind metal cations, forming highly preorganized structures in the process (Northrup et al, 2020). To model this process, the BICePs algorithm was used to reconcile conformational populations from implicitsolvent REMD simulations in GAFF, against sparse experimental ROESY correlations.…”

Section: Modeling Peptoid Foldamersmentioning

confidence: 99%

Reconciling Simulations and Experiments With BICePs: A Review

Voelz

Raddi

2021

Front. Mol. Biosci.

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Bayesian Inference of Conformational Populations (BICePs) is an algorithm developed to reconcile simulated ensembles with sparse experimental measurements. The Bayesian framework of BICePs enables population reweighting as a post-simulation processing step, with several advantages over existing methods, including the proper use of reference potentials, and the estimation of a Bayes factor-like quantity called the BICePs score for model selection. Here, we summarize the theory underlying this method in context with related algorithms, review the history of BICePs applications to date, and discuss current shortcomings along with future plans for improvement.

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Section: Modeling Peptoid Foldamersmentioning

confidence: 99%

Reconciling Simulations and Experiments With BICePs: A Review

Voelz

Raddi

2021

Front. Mol. Biosci.

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“…33 Northrup et al has recently synthesized cyclic hexamers of spiroligomer-peptoid hybrids 36 that can bind monovalent metal cations (Figure 1). 37 The architecture of the macrocycle is highly functionalizable, with alternating spiroligomer and peptoid residues. The portion of the spiroligomer residues participating in the macrocycle backbone resembles a β-substituted proline, which has led to these structures being called "enhanced prolines" or "Q-prolines", while the complete macrocycles are named "Q-proline macrocycles (QPM).…”

Section: Spiroligomer-peptoid Macrocyclesmentioning

confidence: 99%

“…Our modeling correctly ranks the sequence preferences for cationbinding to the macrocycles, and predicts a conformational selection binding model that requires isomerization to an all-trans amide backbone in solution, a conformation distinct from the apo conformation(s) recently obtained from a racemic crystal structure of QPM-3. 37 The methods we present provide a new path towards the rational design of spiroligomer-peptoid macrocycles, and have implications for the general problem of foldamer prediction design.…”

Section: Spiroligomer-peptoid Macrocyclesmentioning

confidence: 99%

“…Three spiroligomer-peptoid macrocycle sequences from Northrup et al 37 were studied in this work; all are three-fold symmetric (Figure 1). Two of the sequences, QPM-1 and QPM-3, were found to bind metal cations in solution.…”

Section: Macrocycle Sequencesmentioning

confidence: 99%

“…1 H-NMR spectra were measured as described in Northrup et al 37 The complex spectra of peptoid macrocycles in solution in the absence of metal cations suggests several slowly interconverting conformations of the macrocycle at equilibrium. In contrast, spectra that were measured for macrocycles in the presence of 100 mM of monovalent trifluoromethylsulfonate (triflate) salts show a remarkable structuring in solution over the course of 12 hours.…”

Section: Nmr Observablesmentioning

confidence: 99%

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Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

Hurley¹,

Northrup²,

Ge³

et al. 2021

Preprint

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<div>The rational design of foldable and functionalizable peptidomimetic scaffolds requires the concerted application of both computational and experimental methods. Recently, a new class of designed peptoid macrocycle incorporating spiroligomer proline mimics (Q-prolines) has been found to pre-organize when bound by monovalent metal cations. To determine the solution-state structure of these cation-bound macrocycles, we employ a Bayesian inference method (BICePs) to reconcile enhanced-sampling molecular simulations with sparse ROESY correlations from experimental NMR studies. The BICePs approach circumvents the need for bespoke force field parameterization, instead relying on experimental restraints to help narrow the possible set of cis/trans amide isomers in solution. Conformations predicted to be most populated in solution were then simulated in the presence of explicit cations to yield trajectories with observed binding events, revealing a highly-preorganized all-trans amide conformation, whose formation is likely limited by the slow rate of cis/trans isomerization. Interestingly, this conformation differs from a racemic crystal structure solved in the absence of cation. Free energies of cation binding computed from distance-dependent potentials of mean force suggest Na+ has higher affinity to the macrocycle than K+, with both cations binding much more strongly in acetonitrile than water. The simulated affinities are able to correctly rank the extent to which different macrocycle sequences exhibit preorganization in the presence of different metal cations and solvents, suggesting our approach is suitable for solution-state computational design.</div>

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Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

Hurley

Northrup

et al. 2021

J. Chem. Inf. Model.

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The rational design of foldable and functionalizable peptidomimetic scaffolds requires the concerted application of both computational and experimental methods. Recently, a new class of designed peptoid macrocycle incorporating spiroligomer proline mimics (Q-prolines) has been found to preorganize when bound by monovalent metal cations. To determine the solution-state structure of these cation-bound macrocycles, we employ a Bayesian inference method (BICePs) to reconcile enhanced-sampling molecular simulations with sparse ROESY correlations from experimental NMR studies to predict and design conformational and binding properties of macrocycles as functional scaffolds for peptidomimetics. Conformations predicted to be most populated in solution were then simulated in the presence of explicit cations to yield trajectories with observed binding events, revealing a highly preorganized all-trans amide conformation, whose formation is likely limited by the slow rate of cis/trans isomerization. Interestingly, this conformation differs from a racemic crystal structure solved in the absence of cation. Free energies of cation binding computed from distance-dependent potentials of mean force suggest Na+ has a higher affinity to the macrocycle than K+, with both cations binding much more strongly in acetonitrile than water. The simulated affinities are able to correctly rank the extent to which different macrocycle sequences exhibit preorganization in the presence of different metal cations and solvents, suggesting our approach is suitable for solution-state computational design.

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Metal-Binding Q-Proline Macrocycles

Cited by 4 publications

References 3 publications

Reconciling Simulations and Experiments With BICePs: A Review

Reconciling Simulations and Experiments With BICePs: A Review

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

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